Cure Research: CROI 2018

By Jeannie Wraight

The Conference on Retroviruses and Opportunistic Infections (CROI) provides an annual snapshot of the year’s most interesting and progressive data on HIV cure and remission research. Here’s a quick run down of some of the highlights presented at this year’s conference.

Kick and Kill
“Kick and kill” is a strategy that proposes to wake up or activate and then eliminate cells that are latently infected with HIV. Active replication allows the immune system to recognize these cells as a danger, making them a target for therapeutic agents. Researchers evaluated in Rhesus monkeys the combination of GS-9620, a TLR antagonist used to activate latent cells, and PGR121, a broadly neutralizing antibody, to kill off the awakened cells. The monkeys had been virally suppressed for two years. ARVs were discontinued before beginning the dual therapy. Viral suppression was maintained for over three months with this combination. At least half the monkeys remained suppressed at six months. In some cases, the virus remerged but the monkeys’ immune systems were able to re-suppress the virus without the need for additional doses. Additionally, researchers found that, even after viral rebound, the virus was at a lower level (viral setpoint) than it had originally been before the monkeys were given the combo, and the monkeys had lower viral DNA levels in their lymph nodes. This study suggests that the duo may have depleted viral reservoirs and allowed for some level of immune control of the virus.

More Validation of U=U
A study relevant to our understanding of viral reservoirs set out to determine if HIV replication occurs in lymph nodes in the presence of viral suppression. Its results are also important to our understanding of the U=U (undetectable equals untransmissable) premise. It has been conclusively established that when a person is undetectable and on sustained treatment for at least six months, he or she can’t transmit HIV to someone else. However, there remains a question as to whether HIV replication occurs elsewhere in the body, such as the lymph nodes, despite it not occurring in the blood, or if ongoing replication in a virally suppressed person stemmed solely from activated latent HIV in viral reservoirs. In this study, Dr. Mary Kearney of NIH’s National Cancer Institute found no evidence of ongoing HIV replication in the lymph node. This study contradicts a previous study published in 2016 that found that HIV replicates in the lymph nodes, helping to replenish viral reservoirs.

CD32+ as a Biomarker?
A major barrier to curing HIV is determining which cells harbor latent HIV. Biomarkers are needed to distinguish latently infected cells from cells not harboring the virus. CD32+ was recently suggested as a biomarker to differentiate the two in CD4 cells. Several studies evaluated this hypothesis and determined CD32+ did not identify latently infected reservoir cells. Studies continue to evaluate other surface markers that can be used as biomarkers, allowing researchers to target these cells.

Early ART in Infants
The “Mississippi baby” first made us aware that very early treatment with ARVs in infants could produce viral suppression for prolonged periods of time. Several studies were conducted to explore the effects of early initiation of ARVs in infants, two of which were reported at CROI 2018. Both studies found that beginning ARVs shortly after birth was safe, feasible and lead to smaller viral reservoirs.

The first study was conducted in Thailand and compared babies aged four to twenty-three weeks who received uninterrupted triple prophylactic ARV therapy since birth and those who did not receive uninterrupted prophylactic ARV therapy. The study also examined virally suppressed babies, with a median age of 2.7 years, who had initiated prophylactic ARV therapy at or after birth. Evaluating markers of HIV persistence, researchers found the infants who received continuous therapy had significantly lower viral loads and lower levels of integrated DNA, than those who didn’t receive continuous therapy. Also lower were the frequency of latently infected cells and the frequencies of cells producing msRNA spontaneously and after stimulation. In the older babies, after ART initiation, those who had started ARVs at birth had significantly lower total and integrated HIV DNA than children starting treatment later and the size of the inducible reservoir correlated with the age at which they began continuous therapy.

In the second study, infants in Botswana were given antiretroviral therapy before the age of seven days old. They were compared to children who started therapy later. Researchers set out to measure immune responses and discover if early treatment limits the size of viral reservoirs and measure immune responses. They found that those treated within seven days had lower viral reservoirs both at the beginning of the study and after eighty-four weeks. Five of the six children who initiated therapy with the first week of life had a negative qualitative HIV DNA PCR and a negative HIV ELISA test after eighty-six weeks.

Originally published in A&U Magazine http://aumag.org/2018/05/21/cure-research-croi-2018/

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A Different Kind of Disease

The unmet need in researching and preventing HIV and Toxoplasmosis co-infection

By David Miller and Chris Romano

The International AIDS Society (IAS) held the world’s largest scientific gathering on HIV science in Paris, France this year, a country where 37% of patients with AIDS have evidence of toxoplasmic encephalitis.

Toxo has been reported as the most common opportunistic infection in HIV/AIDS in developed countries and the most common cause of focal brain lesions, coma and death. It commonly causes encephalitis in HIV-postive patients and increases the risk of HIV Associated Neurological Disorders (HAND) by 60%.

HAND is becoming increasingly prevalent as Anti-Retroviral Therapy (ART) allows HIV patients to live longer lives.  Several poster sessions at IAS 2017 discussed the issue of HAND.

Ei Kinai from the National Center for Global Health and Medicine in Tokyo, Japan presented on The Impact of Age and Time of Disease on HAND.  The study concluded that, “Older patients are more likely to have neurocognitive decline at early stages of HIV infections.”  It is also known that the prevalence of Toxo increases with age, an aspect that was not addressed in the study.

Galia Manuelle Aurora Santos from Lausanne University Hospital Center in Lausanne, Switzerland presented on the link between depressive symptoms and HAND.  This study suggests that addressing depressive symptoms, especially in HIV positive-women, might potentially improve the neurocognitive outcome of HIV-positive  patients.  Toxo has been linked to depression in numerous studies.Vincent Senecal of the Centre de Recherche du CHU de Quebec, Centre de Recherche en Infectiologie, Quebec, Canada shed light on HAND pathogenesis by studying the interactions of HIV with the anti-inflammatory chemokine, fractalkine (FKN). The results indicated that HIV reduced FKN receptor expression in microglia/macrophages which could have important implications in chronic inflammation and immune activation for HAND.  It has been found in separate studies that Toxo also down-regulates FKN after 24 hours of infection.

HAND continues to be a major concern in HIV patients and the connection between HAND and toxo is an understudied issue that may help to better understand and potentially treat HAND. New studies to determine if toxo has a causative effect contributing to neurocognitive decline in people living with HIV are essential.

Toxo infects approximately 1.1 million people each year in the United States. The global prevalence is estimated between 2 and 3 billion and there is no cure.  Acute infection in the immune compromised is often deadly if not aggressively treated with Pyrimethamine (Daraprim).   In 2014, the CDC designated Toxo a Neglected Parasitic Infection (NPI), targeting it for public health action based on the number of people infected and the severity of the disease.  Less than a year later, Martin Shkreli, then CEO of Turing Pharmaceuticals, acquired the rights to Daraprim and raised the price of the now 64 year old drug 5000%, a notorious move that increased an annual prescription to $634,500 for patients weighing more than 60 kilograms (132 pounds).

Without an available cure and considering the unfavorable treatment options at hand, our only immediate hope to alleviate the burden of toxo is to prevent human exposure to the offending pathogen causing the initial disease.

Toxo can only complete its life cycle and produce infectious spores on cat feces.  Most people and animals become infected by unknowingly ingesting or inhaling these spores which makes cleaning a cat’s litter box a high-risk activity, particularly to those who are immune- compromised. Simple precautions should be taken that can eliminate the risk of toxo infection.

Toxo is also transmitted by consuming the raw or rare meat of previously infected animals and is a leading cause of death from foodborne illness in the United States.  The general public is warned of toxo risk by the mandated menu advisory, “Consuming raw or undercooked meats, poultry, seafood, shellfish, eggs or unpasteurized milk may increase your risk of foodborne illness,   But public awareness on how to prevent toxo infections is otherwise extremely limited.

With more than one third of the U.S population sharing their homes with pet cats, the responsibility to provide the warnings and resources necessary to protect the general public from the burdens of toxo and create a safer environment for both humans and cats, should be a high priority of our public health d healthcare systems.

viable solutions to reducing the risk of toxo are essential. One such alternative to using masks and gloves when changing kitty litter is a self-contained cat waste disposal system (created by Toxoplasmosis Solutions, an enterprise of BetterBox) which allows cat owners to safely contain and dispose of domestic cat waste without exposing themselves or their environment to toxo’s infectious spores. Additional tools that the public can utilize including public service announcements on how to properly handle and prepare raw meet, are needed.

Toxo’s life cycle is dependent on cat waste contaminating the environment of its future hosts.  Considering that the majority of cats in the U.S. are domesticated and living in human homes, mechanically blocking the life cycle of this devastating disease by implementing responsible cat waste disposal procedures is an effective option.

Legislators in the U.S. need to be encouraged to develop a national toxoplasmosis bill supporting the additional research, education, prevention, and treatment efforts. The latest scientific findings regarding “latent” toxo along with the compelling epidemiology to inform legislators, public health officials, and health insurance providers that an investment towards designing public awareness has great potential to reduce healthcare costs and disease burden in the United States and globally.

 

 

Questioning the Cure

By Jeannie Wraight and Noreen Griffin

When first discussing the potential of writing a monthly column on HIV cure, my editor here at A&U Magazine asked a very valid question. He wanted to know if I thought I would be able to find enough material for a monthly column. At that time, nearly five years ago, information on cure-related issues was somewhat scarce. This was the main reason I wanted to write Destination: Cure—to be able to gather and report the bits of scattered news, research, and breakthroughs on what was becoming an emerging field of research.

Over the years I’ve had little trouble finding cure-related topics to focus on. In addition to scientific research, there were and still are many political, ethical, social, funding and policy issues that encompass “HIV cure.” Since beginning this column in 2013, I’ve attempted to focus on these issues as they continue to evolve.

A lot has changed since my first column. We’ve come a long way, particularly in HIV reservoir research, scientific collaboration, and heightened funding. However, we still have a vast road ahead of us with many unanswered questions and dilemmas.

For example, how do we know when we’ve found a cure or remission? Several researchers are working on biomarkers that can measure trace amounts of HIV in certain cells and reservoirs. Until these biomarkers are available, it would be difficult to declare a person cured or know if a therapy or cure strategy is successful.

Debate continues about how long a person must remain off ARVs until they are considered in remission. HIV remission is different from an eradication cure, where HIV is completely removed from the body. HIV remission is currently defined similarly to cancer remission in terms of a person being able to remain illness-free without the use of ongoing treatment. Some researchers suggest borrowing the timeframe instituted in cancer patients to define when HIV remission has been achieved. This is normally five years.

Perhaps one of the most important questions that continues to be asked by some is: Do we really still need a cure and is it ethical to continue to search for one? For many this is a no-brainer. However, there are those that argue about the necessity and fairness of spending money on an HIV cure. Some claim that since the approval of over thirty HIV antiretroviral medications have succeeded in turning HIV/AIDS from a deadly disease to a “manageable chronic illness,” that it’s time for HIV to take a backseat to other life- threatening illnesses.

There are over 7,000 “rare diseases” affecting people in the United States. According to a fact sheet from The National Organization for Rare Disorders (NORD), “There are more Americans who live with a rare disease than ALL of those who have either HIV, Heart Disease or Stroke.” Only five percent of rare diseases have FDA-approved treatments. It’s likely that a tiny fraction of the HIV research budget, since the discovery of HIV, could have either cured or found treatments for a number of these diseases.

This argument may be strengthened as U=U and PrEP allow HIV to become untransmittable and easier to protect against, respectively, particularly as ARVs become more available to a greater number of people in the developing world.

So then, is it fair or necessary that such a large amount of resources, including those from government, commercial, foundation and private sector finances, continue to be used for HIV cure and remission efforts?

On an ethical level, few of us are qualified to answer that. However, on a financial level, and in terms of human lives lost, the answer is unequivocally yes.

Despite a massive decrease of forty-eight percent in AIDS-related deaths since the global scale-up of ARVs, there were still 1.1 million deaths from HIV/AIDS-related causes in 2015. Despite over thirty years of research and many HIV therapies, millions of people will continue to die of AIDS and HIV- related illnesses.

The U.S. government currently invests approximately $26 billion domestically, and $6.6 billion globally, to the fight against HIV/AIDS. The need for funding both in the U.S. and abroad is likely to only grow greater with each year. A cure or remission for HIV is the only means of eventually eliminating this financial burden and freeing up funding for other diseases.

As such, the search must continue and questions regarding scientific, ethical, financial and logistic considerations of cure research will need to be fairly, intelligently and timely asked, confronted and resolved. Many questions remain, but as the puzzle slowly takes shape, we must maintain the momentum so many have come together to create.

 

 

The Eastern View from AIDS 2018

By David Miller and Chad Johnson

Many AIDS 2017 attendees in Paris were disappointed by the neglect of a timely, critical focus on the HIV challenges in Venezuela caused by the abject failure of governance, human rights, and the rule of law in Caracas.  With the country falling apart and people unable to obtain essential HIV medications and basic medical supplies, the lack of a concerted effort to address this urgent human tragedy at AIDS 2017 seemed like an astounding failure of the most powerful gathering of stakeholders in the epidemic.  However, an equally pressing dynamic has existed for years without mainstream media coverage in many countries in Eastern Europe and Central Asia (EECA).  While not making the daily headlines, the EECA region has the highest new HIV infection rate in the world at 57% between 2010 and 2015 according to AVERT, a statistic highlighted at the AIDS 2017 teaser session on the upcoming 22nd International AIDS Conference in Amsterdam, Netherlands in July 2018 (AIDS 2018).

The AIDS 2018 session emphasized that one of Amsterdam’s top five objectives is to change the dynamic in the EECA where governments, institutions, orthodox religions, society, law enforcement and criminality, and international organizations fail vulnerable populations.  Session participants noted that this EECA problem was on the agenda during the 19th IAC in Vienna in 2010, a conference now deemed a failure in this regard.  Leading up to AIDS 2010, the WHO reported that the epidemic in Eastern Europe “… can be ascribed to government intransigence, public ignorance and the criminalization of risky behaviors, compounded by poverty, social exclusion and political and economic turmoil.”  These conditions have not significantly changed in Eastern Europe and continued to be mirrored in Central Asia.

Consequently, AIDS 2018 Local Co-Chair Dr. Peter Reiss of Amsterdam and International Co-Chair Dr. Linda Gail-Bekker of Cape Town, South Africa committed to shine a spotlight on people left behind in the international response to the AIDS epidemic and to prompt a vigorous discussion about the reasons that the EECA region is an outlier in the progress seen around the world.  The theme of AIDS 2018, “Breaking Barriers Building Bridges,” speaks to some of the unique contributing factors beyond unsafe sexual practices, including language, culture, lack of human rights and freedom of information, and “relative” prosperity (and with it, non-qualification for various international assistance programs).  Additional factors on the rise in the EECA region include IV drug use in countries disapproving of needle-exchange programs, migration of female sex workers who are shamed into the shadows by conservative societies, and the refugee crisis and its health consequence.

The organizer of the session, the Dutch Ministry of Foreign Affairs, represented by Mr. Lambert Grijus, the Dutch Ambassador for Sexual and Reproductive Health & Rights and HIV/AIDS, articulated rights- and community-based approaches to more effectively reach key populations in the EECA region, along with putting mechanisms in place to hold politicians accountable in regional and international diplomatic settings for shortcomings in HIV-related awareness, funding and policy.  Dr. Michel Kazatchkine, former Director of the Global Fund and currently the UN Secretary-General Special Envoy on HIV/AIDS in Eastern Europe and Central Asia, also underscored the importance of aggressive work with top-level politicians as key to breaking the log jam in the region.  Unless governments acknowledge and take ownership of the growing HIV problem, outside efforts will continue to fail.  In some EECA nations, leaders are in denial that HIV/AIDS even exist in their countries – typifying the difficulties that stand between an increasing epidemic and effective solutions.

On top of government inaction and denial, several avenues of international support are not available as policy enticements since median incomes disqualify funding and assistant for many EECA countries – incomes that are by no means truly prosperous.  Traditional and orthodox populations in rights-limited societies add to the slow demand for and pace of change.  Communication and the free flow of HIV-related information are limited, and a lack of historical commitment to Russian language-based prevention and treatment programs is recognized as a problem for much of the EECA region.

The eastern view from Amsterdam is gloomy but there are glimmers of light.  AIDS 2018 will lead to critical analysis of potential solutions for the epidemic in the EECA.  However, session participants emphasized that the HIV/AIDS community cannot wait until July 2018 to make progress in EECA nations:  lives are at stake, and change is needed now

An Unseen Storm

Despite the success of ARV’s, Toxoplasmosis still remains a serious medical concern for people with HIV/AIDS
By Christopher Romano & Timothy Ray Brown

The protozoan intracellular parasite, toxoplasma gondii (toxo), is still one of the most causative agents of disease and death in HIV/AIDS patients even in the post combination antiretroviral therapy era. Estimates indicate that 30 to 50 percent of humans carry the parasite which often causes toxoplasmic encephalitis in immunocompromised populations. Toxoplasmosis remains profoundly under studied and underfunded as evidenced by the fact no one will be talking about this devastating pathogen at this year’s IAS International Conference on HIV Science.

Continue reading An Unseen Storm

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